Lack of Type VIII Collagen in Mice Ameliorates Diabetic Nephropathy
Ulrike Hopfer 1 ,
Helmut Hopfer 2 ,
Catherine Meyer-Schwesinger 1 ,
Ivonne Loeffler 3 ,
Naomi Fukai 4 ,
Bjorn R. Olsen 4 ,
Rolf A.K. Stahl 1 and
Gunter Wolf 3
1 Department of Medicine, University of Hamburg, Hamburg, Germany;
2 Department of Pathology, University of Hamburg, Hamburg, Germany;
3 Department of Medicine, Friedrich Schiller University, Jena, Germany;
4 Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts.
Corresponding author: Ulrike Hopfer, ulrike.hopfer{at}unibas.ch .
U.H. and H.H. contributed equally to this study.
Abstract
OBJECTIVE Key features of diabetic nephropathy include the accumulation of extracellular matrix proteins. In recent studies, increased
expression of type VIII collagen in the glomeruli and tubulointerstitium of diabetic kidneys has been noted. The objectives
of this study were to assess whether type VIII collagen affects the development of diabetic nephropathy and to determine type
VIII collagen–dependent pathways in diabetic nephropathy in the mouse model of streptozotocin (STZ)-induced diabetes.
RESEARCH DESIGN AND METHODS Diabetes was induced by STZ injections in collagen VIII–deficient or wild-type mice. Functional and histological analyses
were performed 40 days after induction of diabetes. Type VIII collagen expression was assessed by Northern blots, immunohistochemistry,
and real-time PCR. Proliferation of primary mesangial cells was measured by thymidine incorporation and direct cell counting.
Expression of phosphorylated extracellular signal–regulated kinase (ERK1/2) and p27 Kip1 was assessed by Western blots. Finally, Col8a1 was stably overexpressed in mesangial cells.
RESULTS Diabetic wild-type mice showed a strong renal induction of type VIII collagen. Diabetic Col8a1 − / Col8a2 − animals revealed reduced mesangial expansion and cellularity and extracellular matrix expansion compared with the wild type.
These were associated with less albuminuria. High-glucose medium as well as various cytokines induced Col8a1 in cultured mesangial cells. Col8a1 − / Col8a2 − mesangial cells revealed decreased proliferation, less phosphorylation of Erk1/2, and increased p27 Kip1 expression. Overexpression of Col8a1 in mesangial cells induced proliferation.
CONCLUSIONS Lack of type VIII collagen confers renoprotection in diabetic nephropathy. One possible mechanism is that type VIII collagen
permits and/or fosters mesangial cell proliferation in early diabetic nephropathy.
Footnotes
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Received February 10, 2008.
Accepted April 6, 2009.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
© 2009 by the American Diabetes Association....

Lack of Type VIII Collagen in Mice Ameliorates Diabetic Nephropathy

10.2337/db08-0183